CN106458943A - Synthesis of vortioxetine via (2,4-dimethylphenyl)(2-iodophenyl)sulfane intermediate - Google Patents
Synthesis of vortioxetine via (2,4-dimethylphenyl)(2-iodophenyl)sulfane intermediate Download PDFInfo
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- CN106458943A CN106458943A CN201580029392.7A CN201580029392A CN106458943A CN 106458943 A CN106458943 A CN 106458943A CN 201580029392 A CN201580029392 A CN 201580029392A CN 106458943 A CN106458943 A CN 106458943A
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- dimethylphenyl
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- YQNWZWMKLDQSAC-UHFFFAOYSA-N vortioxetine Chemical compound CC1=CC(C)=CC=C1SC1=CC=CC=C1N1CCNCC1 YQNWZWMKLDQSAC-UHFFFAOYSA-N 0.000 title abstract description 6
- ILSSPHBNHOZNHZ-UHFFFAOYSA-N CC1=C(C=CC(=C1)C)SC1=C(C=CC=C1)I Chemical compound CC1=C(C=CC(=C1)C)SC1=C(C=CC=C1)I ILSSPHBNHOZNHZ-UHFFFAOYSA-N 0.000 title abstract description 4
- 229960002263 vortioxetine Drugs 0.000 title abstract description 3
- 230000015572 biosynthetic process Effects 0.000 title description 9
- 238000003786 synthesis reaction Methods 0.000 title description 9
- 238000000034 method Methods 0.000 claims abstract description 56
- 230000008569 process Effects 0.000 claims abstract description 6
- 150000001875 compounds Chemical class 0.000 claims description 86
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 44
- 150000003839 salts Chemical class 0.000 claims description 34
- 239000003054 catalyst Substances 0.000 claims description 22
- 239000010949 copper Substances 0.000 claims description 22
- 238000006243 chemical reaction Methods 0.000 claims description 20
- 238000002360 preparation method Methods 0.000 claims description 20
- 229910052802 copper Inorganic materials 0.000 claims description 17
- LLEMOWNGBBNAJR-UHFFFAOYSA-N biphenyl-2-ol Chemical group OC1=CC=CC=C1C1=CC=CC=C1 LLEMOWNGBBNAJR-UHFFFAOYSA-N 0.000 claims description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 12
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 11
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims description 10
- 239000008194 pharmaceutical composition Substances 0.000 claims description 8
- 229940061334 2-phenylphenol Drugs 0.000 claims description 7
- 235000010292 orthophenyl phenol Nutrition 0.000 claims description 7
- ZVYXEXAXXWINEH-UHFFFAOYSA-N n,n-diethyl-2-hydroxybenzamide Chemical compound CCN(CC)C(=O)C1=CC=CC=C1O ZVYXEXAXXWINEH-UHFFFAOYSA-N 0.000 claims description 6
- 229910052742 iron Inorganic materials 0.000 claims description 5
- 229910052759 nickel Inorganic materials 0.000 claims description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- 229910003202 NH4 Inorganic materials 0.000 claims description 4
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 4
- 229910052788 barium Inorganic materials 0.000 claims description 4
- 229910052792 caesium Inorganic materials 0.000 claims description 4
- 229910052791 calcium Inorganic materials 0.000 claims description 4
- 229910052740 iodine Inorganic materials 0.000 claims description 4
- 229910052744 lithium Inorganic materials 0.000 claims description 4
- 229910052749 magnesium Inorganic materials 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- 229910052700 potassium Inorganic materials 0.000 claims description 4
- 229910052708 sodium Inorganic materials 0.000 claims description 4
- 229910052718 tin Inorganic materials 0.000 claims description 4
- 229910052725 zinc Inorganic materials 0.000 claims description 4
- PFOYYSGBGILOQZ-UHFFFAOYSA-N 2-(2-methylpropanoyl)cyclohexan-1-one Chemical compound CC(C)C(=O)C1CCCCC1=O PFOYYSGBGILOQZ-UHFFFAOYSA-N 0.000 claims description 3
- ROFVEXUMMXZLPA-UHFFFAOYSA-N Bipyridyl Chemical group N1=CC=CC=C1C1=CC=CC=N1 ROFVEXUMMXZLPA-UHFFFAOYSA-N 0.000 claims description 3
- 229910021589 Copper(I) bromide Inorganic materials 0.000 claims description 3
- 229910021591 Copper(I) chloride Inorganic materials 0.000 claims description 3
- 150000001413 amino acids Chemical class 0.000 claims description 3
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 claims description 3
- BERDEBHAJNAUOM-UHFFFAOYSA-N copper(I) oxide Inorganic materials [Cu]O[Cu] BERDEBHAJNAUOM-UHFFFAOYSA-N 0.000 claims description 3
- KRFJLUBVMFXRPN-UHFFFAOYSA-N cuprous oxide Chemical compound [O-2].[Cu+].[Cu+] KRFJLUBVMFXRPN-UHFFFAOYSA-N 0.000 claims description 3
- 150000004985 diamines Chemical class 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 230000009467 reduction Effects 0.000 claims description 3
- IOVCWXUNBOPUCH-UHFFFAOYSA-M Nitrite anion Chemical compound [O-]N=O IOVCWXUNBOPUCH-UHFFFAOYSA-M 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 150000001989 diazonium salts Chemical class 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 7
- 208000019901 Anxiety disease Diseases 0.000 abstract description 4
- 230000036506 anxiety Effects 0.000 abstract description 4
- 229940079593 drug Drugs 0.000 abstract description 3
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 208000020401 Depressive disease Diseases 0.000 abstract 1
- 239000000203 mixture Substances 0.000 description 41
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 35
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 28
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 27
- QZOCQWGVJOPBDK-UHFFFAOYSA-N 2-iodobenzenethiol Chemical compound SC1=CC=CC=C1I QZOCQWGVJOPBDK-UHFFFAOYSA-N 0.000 description 19
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- 229910052763 palladium Inorganic materials 0.000 description 17
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 15
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 15
- 239000005864 Sulphur Substances 0.000 description 15
- 239000000243 solution Substances 0.000 description 15
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 14
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 14
- 238000005160 1H NMR spectroscopy Methods 0.000 description 13
- 239000012044 organic layer Substances 0.000 description 12
- 239000000376 reactant Substances 0.000 description 12
- 238000003756 stirring Methods 0.000 description 12
- -1 bromo-Phenylsulfanyl Chemical group 0.000 description 10
- AMNLXDDJGGTIPL-UHFFFAOYSA-N 2,4-dimethylbenzenethiol Chemical compound CC1=CC=C(S)C(C)=C1 AMNLXDDJGGTIPL-UHFFFAOYSA-N 0.000 description 9
- UBPDKIDWEADHPP-UHFFFAOYSA-N 2-iodoaniline Chemical compound NC1=CC=CC=C1I UBPDKIDWEADHPP-UHFFFAOYSA-N 0.000 description 9
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 239000003513 alkali Substances 0.000 description 9
- 235000019439 ethyl acetate Nutrition 0.000 description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 9
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 description 8
- 238000007872 degassing Methods 0.000 description 8
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 8
- 239000002585 base Substances 0.000 description 7
- 238000010168 coupling process Methods 0.000 description 7
- 238000005859 coupling reaction Methods 0.000 description 7
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 7
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 239000012266 salt solution Substances 0.000 description 7
- FJDQFPXHSGXQBY-UHFFFAOYSA-L Cs2CO3 Substances [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- 230000008878 coupling Effects 0.000 description 6
- 239000003446 ligand Substances 0.000 description 6
- 239000007832 Na2SO4 Substances 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 238000011097 chromatography purification Methods 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- 150000008049 diazo compounds Chemical class 0.000 description 5
- 229910001385 heavy metal Inorganic materials 0.000 description 5
- SNHMUERNLJLMHN-UHFFFAOYSA-N iodobenzene Chemical compound IC1=CC=CC=C1 SNHMUERNLJLMHN-UHFFFAOYSA-N 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- 229910052938 sodium sulfate Inorganic materials 0.000 description 5
- TYHUGKGZNOULKD-UHFFFAOYSA-N 1-fluoro-2-iodobenzene Chemical compound FC1=CC=CC=C1I TYHUGKGZNOULKD-UHFFFAOYSA-N 0.000 description 4
- CZZZABOKJQXEBO-UHFFFAOYSA-N 2,4-dimethylaniline Chemical compound CC1=CC=C(N)C(C)=C1 CZZZABOKJQXEBO-UHFFFAOYSA-N 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 229910000024 caesium carbonate Inorganic materials 0.000 description 4
- 238000006555 catalytic reaction Methods 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- 230000008020 evaporation Effects 0.000 description 4
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L magnesium sulphate Substances [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- 239000012299 nitrogen atmosphere Substances 0.000 description 4
- 239000002798 polar solvent Substances 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical compound SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 description 4
- BFCFYVKQTRLZHA-UHFFFAOYSA-N 1-chloro-2-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1Cl BFCFYVKQTRLZHA-UHFFFAOYSA-N 0.000 description 3
- PWKNBLFSJAVFAB-UHFFFAOYSA-N 1-fluoro-2-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1F PWKNBLFSJAVFAB-UHFFFAOYSA-N 0.000 description 3
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 description 3
- 238000000297 Sandmeyer reaction Methods 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000011575 calcium Substances 0.000 description 3
- 229910000037 hydrogen sulfide Inorganic materials 0.000 description 3
- 239000011777 magnesium Substances 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 230000002194 synthesizing effect Effects 0.000 description 3
- 230000001988 toxicity Effects 0.000 description 3
- 231100000419 toxicity Toxicity 0.000 description 3
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical group [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 3
- 229910000404 tripotassium phosphate Inorganic materials 0.000 description 3
- IVSZLXZYQVIEFR-UHFFFAOYSA-N 1,3-Dimethylbenzene Natural products CC1=CC=CC(C)=C1 IVSZLXZYQVIEFR-UHFFFAOYSA-N 0.000 description 2
- OIRHKGBNGGSCGS-UHFFFAOYSA-N 1-bromo-2-iodobenzene Chemical compound BrC1=CC=CC=C1I OIRHKGBNGGSCGS-UHFFFAOYSA-N 0.000 description 2
- BUNKQJAMHYKQIM-UHFFFAOYSA-N 1-iodo-2,4-dimethylbenzene Chemical compound CC1=CC=C(I)C(C)=C1 BUNKQJAMHYKQIM-UHFFFAOYSA-N 0.000 description 2
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 2
- NXXYKOUNUYWIHA-UHFFFAOYSA-N 2,6-Dimethylphenol Chemical compound CC1=CC=CC(C)=C1O NXXYKOUNUYWIHA-UHFFFAOYSA-N 0.000 description 2
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- UAEPNZWRGJTJPN-UHFFFAOYSA-N Methylcyclohexane Natural products CC1CCCCC1 UAEPNZWRGJTJPN-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- XJXGJNVIGVFKHT-UHFFFAOYSA-N S.[N+](=O)([O-])C1=C(C(=O)C2=CC=CC=C2)C=CC=C1 Chemical compound S.[N+](=O)([O-])C1=C(C(=O)C2=CC=CC=C2)C=CC=C1 XJXGJNVIGVFKHT-UHFFFAOYSA-N 0.000 description 2
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- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropyl acetate Chemical compound CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 2
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- COCAUCFPFHUGAA-MGNBDDOMSA-N n-[3-[(1s,7s)-5-amino-4-thia-6-azabicyclo[5.1.0]oct-5-en-7-yl]-4-fluorophenyl]-5-chloropyridine-2-carboxamide Chemical compound C=1C=C(F)C([C@@]23N=C(SCC[C@@H]2C3)N)=CC=1NC(=O)C1=CC=C(Cl)C=N1 COCAUCFPFHUGAA-MGNBDDOMSA-N 0.000 description 2
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- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
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- 125000006276 2-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C(*)C([H])=C1[H] 0.000 description 1
- SDTMFDGELKWGFT-UHFFFAOYSA-N 2-methylpropan-2-olate Chemical compound CC(C)(C)[O-] SDTMFDGELKWGFT-UHFFFAOYSA-N 0.000 description 1
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- FCSKOFQQCWLGMV-UHFFFAOYSA-N 5-{5-[2-chloro-4-(4,5-dihydro-1,3-oxazol-2-yl)phenoxy]pentyl}-3-methylisoxazole Chemical compound O1N=C(C)C=C1CCCCCOC1=CC=C(C=2OCCN=2)C=C1Cl FCSKOFQQCWLGMV-UHFFFAOYSA-N 0.000 description 1
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- VIMSLSBCIMFRMN-QZYGSXHOSA-N CC(/C(/N1CCNCC1)=C(/C)\C=C/C)Sc1ccc(C)cc1C Chemical compound CC(/C(/N1CCNCC1)=C(/C)\C=C/C)Sc1ccc(C)cc1C VIMSLSBCIMFRMN-QZYGSXHOSA-N 0.000 description 1
- RNVCVTLRINQCPJ-UHFFFAOYSA-N Cc1ccccc1N Chemical compound Cc1ccccc1N RNVCVTLRINQCPJ-UHFFFAOYSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 102100028735 Dachshund homolog 1 Human genes 0.000 description 1
- OTMSDBZUPAUEDD-UHFFFAOYSA-N Ethane Chemical compound CC OTMSDBZUPAUEDD-UHFFFAOYSA-N 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 101000915055 Homo sapiens Dachshund homolog 1 Proteins 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- 239000005909 Kieselgur Substances 0.000 description 1
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 description 1
- 229910004879 Na2S2O5 Inorganic materials 0.000 description 1
- 229910021605 Palladium(II) bromide Inorganic materials 0.000 description 1
- 229910002666 PdCl2 Inorganic materials 0.000 description 1
- 239000004793 Polystyrene Substances 0.000 description 1
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- 108010077895 Sarcosine Proteins 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical compound C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 description 1
- LPQOADBMXVRBNX-UHFFFAOYSA-N ac1ldcw0 Chemical compound Cl.C1CN(C)CCN1C1=C(F)C=C2C(=O)C(C(O)=O)=CN3CCSC1=C32 LPQOADBMXVRBNX-UHFFFAOYSA-N 0.000 description 1
- 229910000272 alkali metal oxide Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 1
- 150000004703 alkoxides Chemical class 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 125000004799 bromophenyl group Chemical group 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 125000005587 carbonate group Chemical group 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 229940125890 compound Ia Drugs 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 239000012973 diazabicyclooctane Substances 0.000 description 1
- FHIVAFMUCKRCQO-UHFFFAOYSA-N diazinon Chemical compound CCOP(=S)(OCC)OC1=CC(C)=NC(C(C)C)=N1 FHIVAFMUCKRCQO-UHFFFAOYSA-N 0.000 description 1
- 125000000664 diazo group Chemical group [N-]=[N+]=[*] 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- VURFVHCLMJOLKN-UHFFFAOYSA-N diphosphane Chemical group PP VURFVHCLMJOLKN-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 238000007172 homogeneous catalysis Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 229910052738 indium Inorganic materials 0.000 description 1
- 238000004255 ion exchange chromatography Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229910052746 lanthanum Inorganic materials 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 229910000474 mercury oxide Inorganic materials 0.000 description 1
- UKWHYYKOEPRTIC-UHFFFAOYSA-N mercury(ii) oxide Chemical compound [Hg]=O UKWHYYKOEPRTIC-UHFFFAOYSA-N 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 239000003863 metallic catalyst Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000011812 mixed powder Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000007339 nucleophilic aromatic substitution reaction Methods 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 229960003540 oxyquinoline Drugs 0.000 description 1
- MUJIDPITZJWBSW-UHFFFAOYSA-N palladium(2+) Chemical compound [Pd+2] MUJIDPITZJWBSW-UHFFFAOYSA-N 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- RYHBGVSBFUOHAE-UHFFFAOYSA-N piperazin-1-ium;bromide Chemical compound Br.C1CNCCN1 RYHBGVSBFUOHAE-UHFFFAOYSA-N 0.000 description 1
- 239000003495 polar organic solvent Substances 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- MCJGNVYPOGVAJF-UHFFFAOYSA-N quinolin-8-ol Chemical compound C1=CN=C2C(O)=CC=CC2=C1 MCJGNVYPOGVAJF-UHFFFAOYSA-N 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 230000036632 reaction speed Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 229940043230 sarcosine Drugs 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- CMXPERZAMAQXSF-UHFFFAOYSA-M sodium;1,4-bis(2-ethylhexoxy)-1,4-dioxobutane-2-sulfonate;1,8-dihydroxyanthracene-9,10-dione Chemical compound [Na+].O=C1C2=CC=CC(O)=C2C(=O)C2=C1C=CC=C2O.CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC CMXPERZAMAQXSF-UHFFFAOYSA-M 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- JYCGXZGGVUKKNQ-UHFFFAOYSA-N tert-butyl formate piperazine Chemical compound C(C)(C)(C)OC=O.N1CCNCC1 JYCGXZGGVUKKNQ-UHFFFAOYSA-N 0.000 description 1
- CWXPZXBSDSIRCS-UHFFFAOYSA-N tert-butyl piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCNCC1 CWXPZXBSDSIRCS-UHFFFAOYSA-N 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 229910052720 vanadium Inorganic materials 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 229910052726 zirconium Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Pain & Pain Management (AREA)
- Psychiatry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention provides a new synthetic process for the production of 1-(2-((2,4-dimethylphenyl)thio)phenyl)piperazine (vortioxetine), a drug for the treatment of depression and anxiety, which is conducted via (2,4-dimethylphenyl)(2-iodophenyl)sulfane intermediate.
Description
Invention field
The present invention relates to for synthesizing depressed medicine 1-(2-((2,4-3,5-dimethylphenyl) sulphur generation) benzene with anxiety for the treatment of
Base) the new and advantageous approach of piperazine (fertile replace Xi Ting (vortioxetine)).
Background of invention
Irrigate and be disclosed in WO 2003/029232 A1 as embodiment 1e for Xi Ting and be described as being similar to embodiment
1 preparation.Method for preparing embodiment 1 relates to preparing 1-(2-((2-(trifluoromethyl) on solid polystyrene holder
Phenyl) sulphur generation) phenyl) piperazine, then use radiation of visible light solution compound (decomplexation), and pass through preparative
LC-MS and ion exchange chromatography.The fertile gross production rate for Xi Ting of preparation is described as 17%.
It is described in the enforcement of WO 2007/144005 A1 for preparing the fertile method for several optional palladium chtalyst of Xi Ting
In example 17-25.These methods describe is passed through 1-by 2,4-dimethylbenzene thiol and 2-bromo-iodobenzene (or 1,2-dibromobenzene) raw material
(the bromo-Phenylsulfanyl of 2-)-2,4-dimethyl-preparation of benzene intermediate is fertile replaces Xi Ting.These methods each relate to use palladium chtalyst
Agent and Phosphine ligands.
The fertile preparation for Xi Ting is also described in J.Med.Chem. (2011) by Bang-Andersen et al., volume 54,
In 3206-3221.In Wen in the first step, Boc-piperazine and 2-bromo-iodobenzene are prepared 4-(2-in the coupling reaction of palladium chtalyst
Bromophenyl) piperazine-1-t-butyl formate intermediate.Then 4-(2-bromophenyl) piperazine-1-t-butyl formate and 2,4-diformazan are made
Base benzenethiol reacts in the presence of palladium catalyst and Phosphine ligands again, provides the fertile of Boc-protection to replace Xi Ting.In final step
In, use hydrochloric acid to make fertile for western spit of fland deprotection, obtain fertile for western spit of fland hydrochloride.
WO2013/102573 A1 describes 1-halogen-2,4-Dimethvl-phenyl, 2-halogen-benzenethiol and optional protection
Reaction in the presence of alkali and palladium catalyst for the piperazine, described palladium catalyst is made up of palladium source and Phosphine ligands.
Said method is individually present defect.Method productivity described in WO 2003/029232 is low and is not suitable for fertile replacing
The extensive preparation of Xi Ting, and WO 2007/144005 A1, WO 2013/102573 A1 and Bang-Andersen et al. is described
Method need to use expensive raw material, palladium catalyst and Phosphine ligands.Additionally, the toxicity of palladium is it is known that Liu et al.
Toxicity of Palladium, Toxicology Letters, 4 (1979) 469-473 and European Medicines
Agency ' s Guideline clearly limit about the specification of metallic catalyst group residue allow every day be exposed to palladium
The amount of (deriving from the palladium residue in medicine), www.ema.europa.eu.Therefore, it is desirable to keep away in the fertile synthesis for Xi Ting
Exempt to use palladium catalyst, and need purification step subsequently to remove palladium residue from final drug products.
Summary of the invention
The many aspects of the present invention, advantage feature and preferred embodiment are summarized respectively in the way of alone or in combination
In following entry, they are made that contribution for solving the purpose of the present invention.
(1) method for preparing Formula VII compound or its salt,
Described method comprises the following steps：
A) Formula V compound is made
React in the presence of copper catalyst with piperazine, and
B) optionally the Formula VII compound obtaining is changed into its salt.
(2) method of entry 1, wherein Cu (I) salt is used as copper catalyst.
(3) method of entry 2, wherein Cu (I) salt is selected from CuI, CuBr, CuCl and Cu2O.
(4) method of entry 2 or entry 3, wherein said copper catalyst also comprises part.
(5) method of entry 4, wherein said part selected from amino acid, bipyridyl, diamines, phenol, alcohol, 1H-BTA,
2-((2,6-3,5-dimethylphenyl) amino)-2-Oxoacetic Acid and 2-isobutyryl cyclohexanone.
(6) method of entry 5, wherein said part is 2-phenylphenol or N, N-diethyl-2-Hydroxylbenzamide.
(7), wherein in step a), there is alkali in the method for entry 1.
Term used herein " alkali " refers to proton accepter, preferably water-soluble protic acceptor or alkoxide, for example alkali gold
Belonging to tert butoxide, more preferably described proton accepter is selected from carbonate and alkali metal or alkaline earth metal hydroxide.Preferred alkali
It is K3PO4、Cs2CO3And K2CO3.
(8) method of entry 7, wherein said alkali is K3PO4.
(9) method of entry 1, wherein step a) is carried out the temperature range of 20 DEG C-200 DEG C.
(10) method of entry 9, wherein said temperature is about 120 DEG C.
Term " about " refer to approximation, in certain interval range, rough or about.When this term and numerical value model
Enclosing when being used in combination, the up-and-down boundary that it enumerates number range by extension changes this scope.Generally, term used herein
" about " numerical value up and down of described value is changed the difference of 10%.
(11) method of entry 1, wherein formula V compound through the following steps：Make compound of formula I
Wherein X represents F or NH2,
React with Formula II compound
(12) method of entry 1, wherein formula V compound through the following steps：Make Formulas I ' compound
With Formula II ' compound reacts
(13) method of entry 12, wherein the method is carried out in the presence of copper catalyst.
(14) method of entry 1, wherein formula V compound through the following steps：Make formula III compound
React with nitrite, and
Make the diazo compound of the formula IV obtaining,
Reacting with formula MI compound, wherein M is selected from K, Na, Li, Cs, Zn, Cu, NH4And Bu4N；Or with formula NI2Compound is anti-
Should, wherein N is selected from Mg, Ca, Ba, Fe, Cu, Ni and Sn；Or and AlI3Reaction.
(15) method of entry 14, wherein makes the diazo compound of the formula IV obtaining and formula MI compound react, wherein M
Selected from K, Na, Li, Cs, Zn, Cu, NH4And Bu4N, preferably M are K.
(16) method of entry 14, wherein makes the diazo compound of formula IV and formula NI obtaining2Compound reacts, wherein
N is selected from Mg, Ca, Ba, Fe, Cu, Ni and Sn.
(17) method of entry 14, wherein prepares formula III compound through the following steps：Make Formulas I " compound
With Formula II " compound reacts,
Wherein Y represents Br or I.
(18) method of entry 14, wherein prepares formula III compound through the following steps：
A) Formulas I is made " ' compound
Wherein Z represents F or Cl,
React with Formula II compound,
Obtain formula III ' compound
B) reduction formula III ' compound, obtain formula III compound.
(19) method of above-mentioned any one of entry, the salt of its compound of formula VTI is hydrobromate or hydrochloride.
(20) Formula V compound
(21) as defined in entry 20, compound is fertile for the purposes in Xi Ting or its salt in preparation.
(22) method of the pharmaceutical composition of Formula VII compound or its salt is comprised for preparation,
The method comprises the following steps：
X) method by carrying out any one of entry 1-19 prepares Formula VII compound or its salt, and
Y) Formula VII compound or its salt and pharmaceutically acceptable carrier and/or excipient are mixed.
New method defined above is without using the homogeneous catalysis of palladium catalyst and Phosphine ligands, former without use costliness
Material just can provide fertile for Xi Ting or its salt with high yield, this method provides industrial applicable, eco-friendly and economical
Upper improvement obtain the fertile method replacing Xi Ting or its salt.Present invention also offers new midbody compound, it is fertile as preparation
Key intermediate for Xi Ting or its salt is highly useful.This intermediate is solid crystal, and it is suitable for optionally through precipitation
Or preferably recrystallization is purified.
Detailed Description Of The Invention
Hereinafter by embodiment, the present invention is described in further detail, but the invention is not restricted to this.
The general theory of the inventive method can represent in scheme 1.
Scheme 1：Typicallying represent of present invention basis synthesis theory.
Formula V compound (i.e. (2,4-3,5-dimethylphenyl) (2-iodophenyl) sulfane) is made to urge at copper with piperazine (Formula IV compound)
React in the presence of agent, form Formula VII compound (fertile for Xi Ting).This reaction can be in the existence of inorganic base or organic base
Under, carry out in polarity or non-polar solven, described inorganic base or organic bases such as K2CO3、Cs2CO3、Na2CO3、K3PO4、
NaOtBu、KOtBu、NaOH、KOH、Et3N、Et2NiPr、Bu3N, triethanolamine, DBU, DABCO etc..Be suitable for solvent be DMSO,
DMF, NMP, twoAlkane, toluene, iPrOH.Reaction temperature should be about 120 in the scope of 20 DEG C-200 DEG C, preferable reaction temperature
℃.
Copper catalyst used is such as Cu (I) salt, such as CuI, CuBr, CuCl or Cu2O.The reaction presenting in scheme 1
Can carry out in the case of not using part.But, when there is part, reaction speed increases.The most frequently used part is amino
Acid, such as proline, glycine, methyl amimoacetic acid (sarcosine), DMG；Bipyridyl；Such as 2,2 '-connection
Pyridine, 1,10-phenanthroline, neocuproine (2,9-dimethyl [1,10] phenanthroline)；Diamines, for example cis-or anti-form-1,2-
DACH, cis-or trans-N, N '-dimethyl-1,2-cyclohexanediamine, 2-methyl-prop-1,2-diamines, N, N '-diformazan
Base ethylenediamine, N, N, N ', N '-tetramethylethylenediamine；Phenol, such as 2,6-xylenol, 2-phenylphenol, 1,1 '-bis-(2-naphthalenes
Phenol), 8-hydroxyquinoline, N, N-diethyl-2-Hydroxylbenzamide；Alcohol, such as second-1,2-glycol, 1,1,1-tri--(hydroxyl first
Base) ethane；With other type of part, such as 1H-BTA, 2-((2,6-Dimethvl-phenyl) amino)-2-Oxoacetic Acid
With 2-isobutyryl cyclohexanone.The part being preferably used is 2-phenylphenol and N, N-diethyl-2-Hydroxylbenzamide.
Optionally, fertile can also change into its salt for western spit of fland compound by what the method for the present invention obtained, for example, convert
Become hydrobromate (VII.HBr) or hydrochloride (VII.HCl).
In special embodiment, Formula V compound can be prepared by the reaction of example in scheme 2.
Scheme 2：The present invention particularly synthesizes the representative of embodiment.
System can be replaced according to the simple nucleophilic aromatic of the fluorine atom in compound Ia and 2,4-dimethylbenzene thiol (II)
Standby intermediate V.Can also be according to Sandmeyer reaction condition, from 2-Iodoaniline (Ib) and 2,4-dimethylbenzene thiol (IIa) is opened
Begin or start to prepare this intermediate V from 2-iodobenzene mercaptan (I ') and 2,4-dimethylaniline (II ').
Or, can also be according to the response path presenting in scheme 3, by 2-((2,4-3,5-dimethylphenyl) sulphur generation) aniline
(III) (2,4-3,5-dimethylphenyl) (2-iodophenyl) sulfane (V), described 2-((2,4-3,5-dimethylphenyl) sulphur generation) aniline are prepared
(III) can be directly by by 2-aminobenzene mercaptan (II ") and 1-bromo-2,4-dimethyl benzene (II " a) or 1-iodo-2,4-diformazan
Base benzene (II " b) coupling, use different types of heavy metal catalyst to prepare, described heavy metal catalyst such as Pd, Cu, Rh,
Co、Fe、Ni、In、La、Zr.The most frequently used heavy metal for this kind of conversion is Pd and Cu.
Can also by 2,4-dimethylbenzene thiol (II) and 1-fluoro-2-nitrobenzene (I " ' a) or 1-chloro-2-nitrobenzene (I " '
B) compound III is prepared.In the first step, (2,4-3,5-dimethylphenyl) (2-nitrobenzophenone) sulfane (III ') is formed, and
In second reactions steps, nitro is reduced into amino.
Scheme 3：The representative synthesizing embodiment especially of the present invention.
Then use Sandmeyer reaction condition that the compound III obtaining as mentioned above is changed into (2,4-dimethyl benzene
Base) (2-iodophenyl) sulfane (V).This process can be by by acid medium such as H2SO4Or HCl joins in the solution of III real
Existing, add inorganic metal nitrite compound, such as NaNO subsequently2.This reaction is in water or water and polar organic solvent example
As in the mixture of MeCN, the temperature range at 0 DEG C-10 DEG C is carried out.Then diazo compound and MI, the NI obtaining is made2Or
AlI3Reaction, wherein M is selected from K, Na, Li, Cs, Zn, Cu, NH4And Bu4N, and wherein N be selected from Mg, Ca, Ba, Fe, Cu, Ni and
Sn.Finally, the temperature at about 25 DEG C obtains Formula V compound.
Said method can by cheap raw material, do not use toxicity palladium catalyst to prepare crystallization of intermediate V.
Scheme 4 presents in special embodiment, makes 1-fluoro-2-iodobenzene (Ia) and 2,4-dimethylbenzene thiol (II)
At the preferred K of alkali2CO3Or Cs2CO3In the presence of, in polar solvent, preferred DMSO or DMF, the reaction temperature of 80 DEG C-200 DEG C
Degree scope is reacted, and preferably this temperature is about 140 DEG C.This reaction i.e. nucleophilic aromatic substitution causes obtaining (2,4-3,5-dimethylphenyl)
(2-iodophenyl) sulfane (V).
Scheme 4：Represent the synthesis of the intermediate V of embodiment of the present invention.
In another the special embodiment presenting in scheme 5, Formula V compound can by 2-Iodoaniline (Ib) or 2,
Prepared by 4-dimethylaniline (II '), first, respectively at about 0 DEG C, compound Ib or II ' is dissolved in acid medium, is preferably solved in HCl
Or H2SO4The aqueous solution.NaNO is added in the solution obtaining2.Finally, it is slowly added into 2 at 0 DEG C subsequently, 4-dimethylbenzene thiol
(II) or the aqueous solution of the sylvite of 2-iodobenzene mercaptan (I ') or sodium salt, compound V is obtained.
Scheme 5：Represent the synthesis of the intermediate V of embodiment of the present invention.
In another special embodiment, by making 2-aminobenzene mercaptan (I ") and 1-iodo-2,4-dimethyl benzene
(II " a) reaction formula V compound (scheme 6).These mixtures use heavy metal catalyst in polar solvent, preferred DMSO
Agent, preferred copper catalyst such as CuI, at the preferred K of alkali2CO3In the presence of coupling, obtain intermediate III.Preferred reaction temperature
It is about 120 DEG C.Then according to standard Sandmeyer reaction condition, compound III is prepared (2,4-3,5-dimethylphenyl) (2-iodobenzene
Base) sulfane (V), first by diazo reagent, preferred NaNO2, at preferred HCl or H of acid2SO4In the presence of, 0 DEG C at water or
Compound III is changed into corresponding diazo compound by the mixture of person's water and the preferred MeCN of polar solvent being suitable for.?
After, it is slowly added into the aqueous solution of KI or sodium iodide in described solutions/mixtures at about 0 DEG C.Can be with fractional crystallization
The compound V of form.
Scheme 6：Represent the synthesis of the intermediate V of embodiment of the present invention.
The fertile Xi Ting (VII) of replacing can be passed through heavy metal catalyst by (2,4-3,5-dimethylphenyl) (2-iodophenyl) sulfane (V)
Prepared by the coupling with piperazine (VI).
As shown in Reference Example 1 and 2, it is possible to use the coupling of Pd-catalysis, obtained fertile for Xi Ting by intermediate V.At this
In coupling process, it is possible to use any palladium (II) source, such as Pddba2、Pd2dba3、Pd(OAc)2、PdCl2、PdBr2Deng.This
Carry out in the presence of conversion is in the presence of phosphine (single phosphine or diphosphine) part and also at Cabbeen type part.For example, Pddba2/
Rac-BINAP can serve as catalysis system.
But, as discussed above, it is desired to avoid using palladium catalyst during synthesis is fertile for western spit of fland and subsequently from finally
Drug products removes the purification step needed for palladium residue.
Therefore, the method according to the invention, Formula V compound and piperazine (VI) coupling in the presence of copper catalyst, its energy
Enough carry out owing to there is more reactive atomic iodine in compound V.
Contrary and as shown in comparing embodiment 1 and 2, if use (2-bromophenyl) (2,4-3,5-dimethylphenyl) sulfane
(V '), then the coupling of Cu-catalysis is inoperative.
In the special embodiment presenting in scheme 7, by make Formula V compound and piperazine (VI) CuI and part,
Preferably 2-phenylphenol or N, in the presence of N-diethyl-2-Hydroxylbenzamide, reaction preparation is fertile replaces Xi Ting (VII).This reaction
Polar solvent, preferably in DMSO, at the preferred K of alkali3PO4In the presence of, carry out the temperature ranges of 20 DEG C-200 DEG C, preferably
Reaction temperature is about 120 DEG C.
Scheme 7：Represent the fertile synthesis for Xi Ting (VII) of the embodiment of the present invention using Cu-ligand catalysis system.
The fertile western spit of fland compound or its salt that replaces prepared in accordance with the present invention, or the form administration with himself can be used,
Preferably as pharmaceutical composition administration, this pharmaceutical composition comprises fertile to replace Xi Ting or its salt and pharmaceutically acceptable figuration
Agent and/or carrier.Furthermore, it is possible to combine prepared in accordance with the present invention irrigating with other medicines for western spit of fland compound or its salt, special
It is not and the medicine for treating depressed and anxiety.
In another aspect of the present invention, preparation comprises the pharmaceutical composition of Formula VII compound (fertile for Xi Ting) or its salt,
By comprising the following steps：Formula VII compound or its salt prepared as described above, and mix Formula VII compound or its salt and medicine
Acceptable carrier and/or excipient on.Can suitably select administration form, be for example adapted for being administered orally, non-bowel, rectum are executed
Form and/or applied by suction, and formulation can be solid, liquid or powder.Therefore, comprise according to the present invention
The fertile pharmaceutical composition for Xi Ting or its salt of preparation can be suitably for Orally administered tablet, pill, capsule, sugar
The form of slurry agent, powder or granule；Or it is the sterile parenteral for parenteral administration or subcutaneous solutions, suspended dosage form
Formula；Or for the suppository form for rectal administration.
The excipient and/or the carrier that are suitable for include but is not limited to diluent, adhesive, disintegrant, lubricant etc..For example,
Compound or its particle that is fractionized or that comprise described compound are mixed with carrier or binder substance, for example monose, two
Sugar or polysaccharide, such as sugar and starch, sugar alcohol or another kind of polyalcohol.For example, lactose, sucrose, sorbierite, mannitol, shallow lake are mixed
Powder, cellulose derivative, adhesive such as polyvinylpyrrolidone and lubricant such as magnesium stearate, calcium stearate, poly-second two
Alcohol, wax, paraffin etc., be then pressed into tablet.Can to compound or it be fractionized or comprise this chemical combination with other material
The granule coating of thing.The mixture of powders comprising described compound or particle formulation can also be entered capsule.
The prepared in accordance with the present invention fertile pharmaceutical composition for Xi Ting or its salt comprising desired amount is generally suitable for controlling
Treat disease or the illness of the patient needing, particularly show desired activity when treatment depression and anxiety.
Another embodiment of the invention there are provided and can be used for synthesizing having in Formula VII compound (fertile for Xi Ting)
The midbody compound V being worth.
The following example is nonrestrictive and for illustrating the present invention.
Test method
Embodiment 1：By 1-fluoro-2-nitrobenzene (I " ' a) or 1-chloro-2-nitrobenzene (I " ' b) and 2,4-dimethylbenzene thiol
(II) 2-((2,4-3,5-dimethylphenyl) sulphur generation) aniline (III), then nitro reduction are prepared.
Under 25 DEG C of stirrings, to K2CO3(125g, 0.90mol) mixture in dry DMF (0.5L) is slowly added into
2,4-dimethylbenzene thiol II (113mL, 0.84mol), then added 1-fluoro-2-nitrobenzene I in 2 hours " ' a (116g,
0.82mol).After this reactant mixture is stirred 30 minutes, add 1L water, and it is little that at 25 DEG C, the mixture obtaining is stirred 1
When.It is then filtered off yellow mercury oxide, wash with water (2 × 0.5L), and 50 DEG C of vacuum drying, obtain title compound
III ', is yellow crystal (209g, 98% productivity)：DSC：Start 93.34 DEG C, peak value 97.39 DEG C；1H NMR(CDCl3,
500MHz) δ 2.30 (s, 3H), 2.40 (s, 3H), 6.71 (dd, J=1.2,8.2Hz, 1H), 7.11 (m, 1H), 7.18-7.22
(m, 2H), 7.32 (m, 1H), 7.46 (d, J=7.8Hz, 1H), 8.25 (dd, J=1.4,8.2Hz, 1H)；MS(ESI)m/z：260
[MH]+.
To 1-chloro-2-nitrobenzene I " ' solution in dry DMF (30mL) for the b (5.00g, 31.7mmol) adds K2CO3
(5.26g, 38mmol) and 2,4-dimethylbenzene thiol II (4.50mL, 33.3mmol), and the reactant mixture producing is existed
25 DEG C are stirred 18 hours.Add water (60mL), and the mixture obtaining is stirred 30 minutes at 25 DEG C.It is then filtered off yellow
Precipitation, is washed by water (2 × 50mL), and is dried, and obtains title compound III ', is yellow crystal (8.24g, gross production rate)：1H NMR(CDCl3, 500MHz) δ 2.30 (s, 3H), 2.40 (s, 3H), 6.71 (dd, J=1.2,8.2Hz, 1H), 7.11 (m,
1H), 7.18-7.22 (m, 2H), 7.32 (m, 1H), 7.46 (d, J=7.8Hz, 1H), 8.25 (dd, J=1.4,8.2Hz, 1H)；
MS(ESI)m/z：260[MH]+.
To (2,4-3,5-dimethylphenyl) (2-nitrobenzophenone) sulfane III's ' (10.0g, 38.6mmol) and AcOH (100mL)
Mixture adds Fe (8.61g, 154mmol), and the reactant mixture producing is stirred 16 hours at 30 DEG C.Then will be anti-
Mixture is answered to be filtered by bed of diatomaceous earth, and concentrated filtrate.The saturated NaHCO of 300mL is added in residue3And 100mL
EtOAc.Separate organic layer, wash organic layer with EtOAc (100mL), through Na2SO4It is dried the organic layer merging, and evaporate molten
Agent, obtains title compound III, is orange (8.85g, 99% productivity)：1HNMR(CDCl3,500MHz)δ2.28(s,
3H), 2.40 (s, 3H), 4.24 (br s, 2H), 6.71 (d, J=8.1Hz, 1H), 6.75-6.81 (m, 2H), 6.87 (m, 1H),
7.02 (m, 1H), 7.23 (m, 1H), 7.38 (dd, J=1.5,7.7Hz, 1H)；MS(ESI)m/z：230[MH]+.
Embodiment 2：2-aminobenzene mercaptan (I ") is prepared 2-((2,4-3,5-dimethylphenyl) sulphur generation) aniline (III)
By 2-aminobenzene mercaptan I " (1.07mL, 10.0mmol), 1-iodo-2,4-dimethyl benzene II " a (1.43mL,
10.0mmol), CuI (0.19g, 1.0mmol), K2CO3The mixing of the DMSO (50mL) of (6.90g, 50.0mmol) and dry degassing
Thing stirs 16 hours at 120 DEG C in nitrogen.Reactant mixture is cooled to room temperature, adds water (50mL), and product is extracted
It is taken into EtOAc (2 × 150mL).Wash the organic layer merging with water (3 × 150mL) and salt solution (3 × 150mL).Then warp
MgSO4It is dried organic phase, and evaporates solvent, obtain title compound, be dark oil thing (2.15g, 94% productivity)：1H
NMR(CDCl3, 500MHz) and δ 2.28 (s, 3H), 2.40 (s, 3H), 4.24 (br s, 2H), 6.71 (d, J=8.1Hz, 1H),
6.75-6.81 (m, 2H), 6.87 (m, 1H), 7.02 (m, 1H), 7.23 (m, 1H), 7.38 (dd, J=1.5,7.7Hz, 1H)；MS
(ESI)m/z：230[MH]+.
Embodiment 3：2-((2,4-3,5-dimethylphenyl) sulphur generation) aniline (III) is prepared (2,4-3,5-dimethylphenyl) (2-iodine
Phenyl) sulfane (V)
In 2-((2,4-3,5-dimethylphenyl) sulphur generation) mixture in water (8mL) for the aniline III (1.83g, 8.0mmol)
It is slowly added into H2SO4(96%, 1.2mL).The mixture obtaining is cooled to 0 DEG C, and is slowly added into NaNO2(0.61g,
8.8mmol) the solution in water (2mL).Add after completing, add MeCN (5mL), and the mixture obtaining is stirred at 0 DEG C
Mix 30 minutes.Then this solution is slowly added in ice-cold KI (1.74g, the 10.5mmol) aqueous solution (4mL water).Will
The mixture arriving stirs 16 hours at 25 DEG C.Be subsequently adding EtOAc (20mL), separate organic layer, with water (3 × 50mL) and
Na2S2O5(aqueous solution, 25mL) washs, and is included C (1g) and the MgSO of silica gel (1g)4It is dried.It is then filtered off salt, use
EtOAc washs, and concentrated filtrate, obtains title compound V, is orange, and (2.47g, 91% produces in crystallization during standing
Rate)：1H NMR(CDCl3, 500MHz) and δ 2.33 (s, 3H), 2.37 (s, 3H), 6.58 (dd, J=1.5,8.0Hz, 1H), 6.81
(m, 1H), 7.06 (m, 1H), 7.13 (m, 1H), 7.17 (m, 1H), 7.39 (d, J=7.8Hz, 1H), 7.80 (dd, J=1.3,
7.8Hz,1H)；MS(ESI)m/z：341[MH]+.
Embodiment 4：1-fluoro-2-iodobenzene (Ia) is prepared (2,4-3,5-dimethylphenyl) (2-iodophenyl) sulfane (III)
By fluoro-for 1-2-iodobenzene Ia (0.58mL, 5.0mmol), 2,4-dimethylbenzene thiol II (0.68mL, 5.0mmol) and
Cs2CO3(1.71g, 5.25mmol) mixture in the DMF (2mL) of dry degassing stirs 3 days at 140 DEG C in nitrogen.Will
Reactant mixture is cooled to room temperature, is subsequently adding water (25mL), and product is extracted into EtOAc (2 × 20mL).With salt solution (2
× 20mL) wash the organic layer merging, and through MgSO4It is dried.After evaporation solvent, separate title compound V, at brown oil
Thing (1.29g, 75% productivity)：1H NMR(CDCl3, 500MHz) δ 2.33 (s, 3H), 2.37 (s, 3H), 6.58 (dd, J=1.5,
8.0Hz, 1H), 6.81 (m, 1H), 7.06 (m, 1H), 7.13 (m, 1H), 7.17 (m, 1H), 7.39 (d, J=7.8Hz, 1H),
7.80 (dd, J=1.3,7.8Hz, 1H)；MS(ESI)m/z：341[MH]+.
Embodiment 5：2-Iodoaniline (Ib) is prepared (2,4-3,5-dimethylphenyl) (2-iodophenyl) sulfane (III)
Be slowly added in the mixture of ice (2.5g) and 37%HCl (2.1mL) 2-Iodoaniline Ib (2.74g,
12.5mmol).It after the mixture obtaining is stirred 15 minutes at 0 DEG C, is slowly added into NaNO2(0.88g, 12.75mmol) water
Solution (2.15mL water).When the solution that will obtain 0 DEG C stirring 30 minutes while, preparation KOH (2.8g, 50.0mmol), 2,
Solution in water (5mL) for 4-dimethylbenzene thiol II (2.03mL, 15.0mmol).It is slowly added in this solution and make in advance
The standby solution containing diazol.The reactant mixture obtaining is stirred 1 hour at 5 DEG C, is then heated to 80 DEG C, and stirs
Mix 20 hours.Then reactant mixture is cooled to room temperature, adds water (20mL), and product is extracted into MeTHF (2 ×
20mL).Wash the organic layer merging with 1M HCl (3 × 20mL) and salt solution (2 × 20mL).Separate organic phase, through MgSO4Dry
Dry, and evaporate solvent.The crude product (MeCy) being obtained by chromatography purification, obtains title compound, is orange
(2.35g, 55% productivity)：1H NMR(CDCl3, 500MHz) δ 2.33 (s, 3H), 2.37 (s, 3H), 6.58 (dd, J=1.5,
8.0Hz, 1H), 6.81 (m, 1H), 7.06 (m, 1H), 7.13 (m, 1H), 7.17 (m, 1H), 7.39 (d, J=7.8Hz, 1H),
7.80 (dd, J=1.3,7.8Hz, 1H)；MS(ESI)m/z：341[MH]+.
Embodiment 6：2-iodobenzene mercaptan (I ') is prepared (2,4-3,5-dimethylphenyl) (2-iodophenyl) sulfane (V)
To H2SO4The mixture of (96%, 2.0mL) and water (10mL) is slowly added into 2,4-dimethylaniline II '
(1.54mL, 12.5mmol).It after being cooled to 0 DEG C, is slowly added into NaNO2(0.88g, 12.75mmol).Stir 30 points at 0 DEG C
Zhong Hou, is slowly added into ice-cold 2-iodobenzene mercaptan (I ') (3.0g, 12.75mmol) and KOH (5.6g, 100mmol)
In solution in water (15mL).The reactant mixture that obtains is stirred 1 hour at 5 DEG C, is subsequently adding MeCN (20mL), by molten
Liquid is heated to 70 DEG C, and stirs 16 hours.It is subsequently adding water (50mL), product is extracted into EtOAc (3 × 25mL), warp
MgSO4It is dried the organic layer merging.After evaporation solvent, by chromatography purification crude product (MeCy), obtain title compound, be
Orange, crystallizes (2.60g, 61% productivity) during standing：1H NMR(CDCl3,500MHz)δ2.33(s,3H),2.37(s,
3H), 6.58 (dd, J=1.5,8.0Hz, 1H), 6.81 (m, 1H), 7.06 (m, 1H), 7.13 (m, 1H), 7.17 (m, 1H), 7.39
(d, J=7.8Hz, 1H), 7.80 (dd, J=1.3,7.8Hz, 1H)；MS(ESI)m/z：341[MH]+.
Embodiment 7：The preparation of 1-(2-((2,4-3,5-dimethylphenyl) sulphur generation) phenyl) piperazine (fertile for Xi Ting, VII)
By (2,4-3,5-dimethylphenyl) (2-iodophenyl) sulfane V (0.34g, 1.0mmol), piperazine VI (0.13g,
1.5mmol)、K3PO3(0.42g, 2.0mmol), CuI (19mg, 0.1mmol) and 2-phenylphenol (68mg, 0.4mmol) are being done
Mixture in the DMSO (2mL) of dry degassing heats 20 hours at 120 DEG C in nitrogen atmosphere.It is subsequently adding water (10mL), and
And product is extracted into EtOAc (3 × 10mL).Wash the organic layer merging with water (3 × 10mL) and salt solution (2 × 10mL), and
And through Na2SO4It is dried.After evaporation solvent, by chromatography purification crude product, obtain title compound：1H NMR(CDCl3,
500MHz)δ1.63(br s,1H),2.33(s,3H),2.37(s,3H),3.02-3.09(m,8H),6.52(m,1H),6.87
(m, 1H), 7.04 (m, 1H), 7.06-7.10 (m, 2H), 7.16 (m, 1H), 7.39 (d, J=7.8Hz, 1H)；MS(ESI)m/z：
299[MH]+.
Embodiment 8：The preparation of 1-(2-((2,4-3,5-dimethylphenyl) sulphur generation) phenyl) piperazine (fertile for Xi Ting, VII)
By (2,4-3,5-dimethylphenyl) (2-iodophenyl) sulfane V (0.34g, 1.0mmol), piperazine VI (0.13g,
1.5mmol)、K3PO3(0.42g, 2.0mmol), CuI (19mg, 0.1mmol) and N, N-diethyl-2-Hydroxylbenzamide
(39mg, 0.2mmol) mixture in the DMSO (2mL) of dry degassing heats 20 hours at 120 DEG C in nitrogen atmosphere.So
Rear addition water (10mL), and product is extracted into EtOAc (3 × 10mL).Washed by water (3 × 10mL) and salt solution (2 × 10mL)
Wash the organic layer of merging, and through Na2SO4It is dried.After evaporation solvent, by chromatography purification crude product, obtain title compound
Thing：1H NMR(CDCl3,500MHz)δ1.63(br s,1H),2.33(s,3H),2.37(s,3H),3.02-3.09(m,8H),
6.52 (m, 1H), 6.87 (m, 1H), 7.04 (m, 1H), 7.06-7.10 (m, 2H), 7.16 (m, 1H), 7.39 (d, J=7.8Hz,
1H)；MS(ESI)m/z：299[MH]+.
Embodiment 9：1-(2-((2,4-3,5-dimethylphenyl) sulphur generation) phenyl) piperazine hydrobromide (it is fertile for western spit of fland HBr,
VII.HBr) preparation
It is slowly added into fertile replacing in solution in iPrOAc (20mL) for the western spit of fland VII (1.80g, 6.03mmol) in room temperature
48%HBr (0.68mL, 6.03mmol).The mixture obtaining is stirred at room temperature 1 hour, is then filtered off white precipitate, use
Acetone (2 × 20mL) washs, and is dried, and obtains title compound VII.HBr, is white powder (2.15g, 94% productivity)：1H NMR(DMSO-d6,500MHz)δ2.23(s,3H),2.32(s,3H),3.15-3.27(m,8H),6.40(m,1H),6.96
(m, 1H), 7.08-7.17 (m, 3H), 7.24 (m, 1H), 7.32 (d, J=7.8Hz, 1H), 8.85 (br, 2H).
Comparative Examples 1：The preparation of 1-(2-((2,4-3,5-dimethylphenyl) sulphur generation) phenyl) piperazine (fertile for Xi Ting, VII)
By piperazine (1.0g, 11.6mmol), NaOtBu (1.37g, 13.8mmol), Pddba2(40mg, 0.07mmol) and
Double (2,6-bis--isopropyl phenyl) imidazoles of 1,3-Hydrochloride (24mg, 0.07mmol) is in the toluene (10mL) of dry degassing
Mixture be stirred at room temperature 1 hour.Be subsequently adding (2,4-3,5-dimethylphenyl) (2-iodophenyl) sulfane V (1.32g,
3.86mmol), reactant mixture is heated to 100 DEG C, and stirs 24 hours.After being cooled to room temperature, to this reactant mixture
Middle addition water (5mL) and diatomite (0.4g).After stirring 20 minutes, filter out salt, separate organic layer, with salt solution (2 × 10mL)
Washing, through Na2SO4It is dried, and evaporates solvent, obtain crude product, then pass through chromatography purification, obtain title compound, be
Pale yellow crystals：1H NMR(CDCl3,500MHz)δ1.63(brs,1H),2.33(s,3H),2.37(s,3H).
Comparative Examples 2：The preparation of 1-(2-((2,4-3,5-dimethylphenyl) sulphur generation) phenyl) piperazine (fertile for Xi Ting, VII)
By piperazine (1.29g, 15.0mmol), NaOtBu (1.77g, 17.8mmol), Pddba2 (52mg, 0.09mmol) and
Mixture in the toluene (10mL) of dry degassing for the rac-BINAP (93mg, 0.15mmol) is stirred at room temperature 1 hour.Then
Add (2,4-3,5-dimethylphenyl) (2-iodophenyl) sulfane V (1.70g, 5.0mmol), this reactant mixture be heated to 100 DEG C,
And stir 24 hours.After being cooled to room temperature, in this reactant mixture, add water (5mL) and diatomite (0.4g).Stirring 20
After Fen Zhong, filter out salt, separate organic layer, with salt solution (2 × 10mL) washing, through Na2SO4It is dried, and evaporates solvent, obtain
Product, is orange (1.41g, 95% productivity)：1H NMR(CDCl3,500MHz)δ1.63(br s,1H),2.33(s,
3H),2.37(s,3H),3.02-3.09(m,8H),6.52(m,1H),6.87(m,1H),7.04(m,1H),7.06-7.10(m,
2H), 7.16 (m, 1H), 7.39 (d, J=7.8Hz, 1H)；MS(ESI)m/z：299[MH]+.
Comparing embodiment 1：The preparation of 1-(2-((2,4-3,5-dimethylphenyl) sulphur generation) phenyl) piperazine (fertile for Xi Ting, VII)
By (2,4-3,5-dimethylphenyl) (2-bromophenyl) sulfane V ' (0.29g, 1.0mmol), piperazine VI (0.13g,
1.5mmol)、K3PO3(0.42g, 2.0mmol), CuI (19mg, 0.1mmol) and 2-phenylphenol (68mg, 0.4mmol) are being done
Mixture in the DMSO (2mL) of dry degassing heats 20 hours at 120 DEG C in nitrogen atmosphere.Do not formed fertile for western spit of fland VII.
Comparing embodiment 2：The preparation of 1-(2-((2,4-3,5-dimethylphenyl) sulphur generation) phenyl) piperazine (fertile for Xi Ting, VII)
By (2,4-3,5-dimethylphenyl) (2-bromophenyl) sulfane V ' (0.29g, 1.0mmol), piperazine VI (0.13g,
1.5mmol)、K3PO3(0.42g, 2.0mmol), CuI (19mg, 0.1mmol) and N, N-diethyl-2-Hydroxylbenzamide
(39mg, 0.2mmol) mixture in the DMSO (2mL) of dry degassing heats 20 hours at 120 DEG C in nitrogen atmosphere.No
Formed fertile for western spit of fland VII.
Claims (15)
1. the method for preparing Formula VII compound or its salt,
Described method comprises the following steps：
A) Formula V compound is made
React in the presence of copper catalyst with piperazine, and
B) optionally the Formula VII compound obtaining is changed into its salt.
2. the process of claim 1 wherein that Cu (I) salt is used as copper catalyst.
3. the method for claim 2, wherein Cu (I) salt is selected from CuI, CuBr, CuCl and Cu2O.
4. the method for claim 2 or claim 3, wherein said copper catalyst also comprises part.
5. the method for claim 4, wherein said part selected from amino acid, bipyridyl, diamines, phenol, alcohol, 1H-BTA,
2-((2,6-3,5-dimethylphenyl) amino)-2-Oxoacetic Acid and 2-isobutyryl cyclohexanone.
6. the method for claim 5, wherein said part is 2-phenylphenol or N, N-diethyl-2-Hydroxylbenzamide.
7. the process of claim 1 wherein that Formula V compound is prepared through the following steps：Make compound of formula I
Wherein X represents F or NH2,
React with Formula II compound
8. the process of claim 1 wherein that Formula V compound is prepared through the following steps：Make Formulas I ' compound
With Formula II ' compound reacts,
9. the process of claim 1 wherein that Formula V compound is prepared through the following steps：Make formula III compound
React with nitrite, and
Make the formula IV obtaining ' diazonium compound
Reacting with formula MI compound, wherein M is selected from K, Na, Li, Cs, Zn, Cu, NH4 and Bu4N；Or with formula NI2Compound reacts,
Wherein N is selected from Mg, Ca, Ba, Fe, Cu, Ni and Sn；Or and AlI3Reaction.
10. the method for claim 9, its compound of formula III is prepared through the following steps：Make Formulas I " compound
With Formula II " compound reacts
Wherein Y represents Br or I.
The method of 11. claims 9, its compound of formula III is prepared through the following steps：
A) Formulas I is made " ' compound
Wherein Z represents F or Cl,
React with Formula II compound
Obtain formula III ' compound
B) reduction formula III ' compound, obtain formula III compound.
The method of 12. any one of the claims, the salt of its compound of formula VTI is hydrobromate or hydrochloride.
13. Formula V compounds
14. compounds as defined in claim 13 are in the fertile purposes replaced in Xi Ting or its salt of preparation.
15. for the method preparing pharmaceutical composition, and described pharmaceutical composition comprises Formula VII compound or its salt
The method comprises the following steps：
X) method by carrying out any one of claim 1-12 prepares Formula VII compound or its salt, and
Y) Formula VII compound or its salt and pharmaceutically acceptable carrier and/or excipient are mixed.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP14163774.4 | 2014-04-07 | ||
| EP14163774.4A EP2930171A1 (en) | 2014-04-07 | 2014-04-07 | Synthesis of vortioxetine via (2,4-dimethylphenyl)(2-iodophenyl)sulfane intermediate |
| PCT/EP2015/057444 WO2015155153A1 (en) | 2014-04-07 | 2015-04-07 | Synthesis of vortioxetine via (2,4-dimethylphenyl)(2-iodophenyl)sulfane intermediate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN106458943A true CN106458943A (en) | 2017-02-22 |
| CN106458943B CN106458943B (en) | 2019-05-03 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201580029392.7A Expired - Fee Related CN106458943B (en) | 2014-04-07 | 2015-04-07 | Vortioxetine is synthesized by (2,4- 3,5-dimethylphenyl) (2- iodophenyl) sulfane intermediate |
Country Status (3)
| Country | Link |
|---|---|
| EP (1) | EP2930171A1 (en) |
| CN (1) | CN106458943B (en) |
| WO (1) | WO2015155153A1 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110452188A (en) * | 2019-09-12 | 2019-11-15 | 蚌埠学院 | A kind of preparation method lying prostrate sulphur Xi Ting |
| CN112424177A (en) * | 2018-06-20 | 2021-02-26 | Vio制药公司 | One-pot organic pseudo-catalytic C-H activation method for preparing vortioxetine and vortioxetine intermediate |
| CN115368318A (en) * | 2022-06-22 | 2022-11-22 | 山东辰龙药业有限公司 | Synthetic method and application of vortioxetine |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20180072690A1 (en) * | 2015-03-26 | 2018-03-15 | Cipla Limited | Methods for Making Serotonin Reuptake Inhibitors |
| CN105367516A (en) * | 2015-11-11 | 2016-03-02 | 北京万全德众医药生物技术有限公司 | Novel preparation method of vortioxetine |
| CN109071374A (en) * | 2016-02-08 | 2018-12-21 | Aaa化学公司 | The arylation of fatty amine |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004087662A1 (en) * | 2003-04-04 | 2004-10-14 | H. Lundbeck A/S | 4-(2-phenylsulfanyl-phenyl)-1,2,3,6-tetrahydropyridine derivatives as serotonin reuptake inhibitors |
| WO2007144005A1 (en) * | 2006-06-16 | 2007-12-21 | H. Lundbeck A/S | 1- [2- (2, 4-dimethylphenylsulfanyl) -phenyl] piperazine as a compound with combined serotonin reuptake, 5-ht3 and 5-ht1a activity for the treatment of cognitive impairment |
| WO2009062517A1 (en) * | 2007-11-13 | 2009-05-22 | H. Lundbeck A/S | Therapeutic uses of compounds having combined sert, 5-ht3 and 5-ht1a activity |
| CN104098530A (en) * | 2014-08-07 | 2014-10-15 | 段希福 | Preparation method of Vortioxetine |
| CN104356092A (en) * | 2014-11-27 | 2015-02-18 | 合肥创新医药技术有限公司 | Preparation method for vortioxetine |
| CN104447621A (en) * | 2013-09-18 | 2015-03-25 | 上海华飞医药科技有限公司 | Preparation method of Vortioxetine |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| UA81749C2 (en) | 2001-10-04 | 2008-02-11 | Х. Луннбек А/С | Derivated of phenylpiperazine as serotonin reuptake inhibitorS |
| DK2800746T3 (en) | 2012-01-03 | 2019-05-20 | H Lundbeck As | METHOD FOR PREPARATION OF 1- [2- (2,4-DIMETHYL-PHENYLSULPHANYL) -PHENYL] -PIPERAZINE |
-
2014
- 2014-04-07 EP EP14163774.4A patent/EP2930171A1/en not_active Ceased
-
2015
- 2015-04-07 CN CN201580029392.7A patent/CN106458943B/en not_active Expired - Fee Related
- 2015-04-07 WO PCT/EP2015/057444 patent/WO2015155153A1/en active Application Filing
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004087662A1 (en) * | 2003-04-04 | 2004-10-14 | H. Lundbeck A/S | 4-(2-phenylsulfanyl-phenyl)-1,2,3,6-tetrahydropyridine derivatives as serotonin reuptake inhibitors |
| WO2007144005A1 (en) * | 2006-06-16 | 2007-12-21 | H. Lundbeck A/S | 1- [2- (2, 4-dimethylphenylsulfanyl) -phenyl] piperazine as a compound with combined serotonin reuptake, 5-ht3 and 5-ht1a activity for the treatment of cognitive impairment |
| WO2009062517A1 (en) * | 2007-11-13 | 2009-05-22 | H. Lundbeck A/S | Therapeutic uses of compounds having combined sert, 5-ht3 and 5-ht1a activity |
| CN104447621A (en) * | 2013-09-18 | 2015-03-25 | 上海华飞医药科技有限公司 | Preparation method of Vortioxetine |
| CN104098530A (en) * | 2014-08-07 | 2014-10-15 | 段希福 | Preparation method of Vortioxetine |
| CN104356092A (en) * | 2014-11-27 | 2015-02-18 | 合肥创新医药技术有限公司 | Preparation method for vortioxetine |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112424177A (en) * | 2018-06-20 | 2021-02-26 | Vio制药公司 | One-pot organic pseudo-catalytic C-H activation method for preparing vortioxetine and vortioxetine intermediate |
| CN112424177B (en) * | 2018-06-20 | 2024-05-03 | Vio制药公司 | One-pot organic pseudo-catalytic C-H activation method for preparing vortioxetine and vortioxetine intermediate |
| CN110452188A (en) * | 2019-09-12 | 2019-11-15 | 蚌埠学院 | A kind of preparation method lying prostrate sulphur Xi Ting |
| CN115368318A (en) * | 2022-06-22 | 2022-11-22 | 山东辰龙药业有限公司 | Synthetic method and application of vortioxetine |
| CN115368318B (en) * | 2022-06-22 | 2023-11-03 | 山东辰龙药业有限公司 | Synthesis method and application of voathixetine |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2015155153A1 (en) | 2015-10-15 |
| EP2930171A1 (en) | 2015-10-14 |
| CN106458943B (en) | 2019-05-03 |
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